Our long-term objectives are to increase the understanding of genetic and physiological mechanisms underlying thrombocytopenia and cardiomyopathy. Approximately 8 million units of platelets are transfused in the United States each year as a consequence of low platelet counts or defects in platelet function. Thrombocytopenia remains a major cause of morbidity in cancer patients. The understanding of basic mechanisms that underlie heritable thrombocytopenia in humans has been facilitated by investigations of genetically determined platelet disorders in experimental animals. Mice bearing spontaneous mutations have been studied extensively as models for human diseases and have provided valuable tools with which to clarify basic physiological processes. We have discovered a new spontaneous mutation named "thrombocytopenia and cardiomyopathy" (tac) and have mapped this mutation to a 5 cM interval (5.1 mb) on mouse Chromosome 17. Homozygosity for this mutation causes a 20-fold reduction in platelet numbers, accompanied by a three-fold increase in platelet volume. When maintained on a diet with slightly elevated sodium, tac/tac mice also develop cardiomyopathy. We hypothesize that identification of the molecular basis of this mutation will reveal a novel gene that plays a critical role in platelet production and in the homeostasis of cardiomyocytes in normal and pathologic states. The proposed research focuses on the identification of the tac mutation and on the determination of mechanisms underlying the severe thrombocytopenia. Specific Aim 1 is to identify the molecular basis of the tac mutation using high-resolution mapping, molecular screening of candidate genes, molecular characterization of the mutation, and verification of its causative nature. Specific Aim 2 is to determine mechanisms of underlying thrombocytopenia by analyses of the effects of the tac mutation on megakaryocyte development and on platelet production, lifespan, sequestration, and autoimmune destruction. Reciprocal bone marrow transfers will discriminate between defects that are intrinsic to hematopoietic progenitors and abnormalities in the hematopoietic microenvironment.